Nuclear receptor (NR) signaling is essential for normal development as well as normal metabolic and physiologic function in humans. In addition, NRs are potential targets in a variety of human diseases. Central to the action of NRs is their ability to recruit the transcriptional co-repressors, nuclear receptor co-represor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptors (SMRT), in the absence of ligand or in the presence of antagonists to target key pathways. In the following proposal we will use novel mouse models to understand how NCoR and SMRT specifically interact with target NRs in vivo. In particular we will focus on the thyroid hormone receptor (TR) and the liver x receptor (LXR) to understand the role of the co-repressors in vivo as we have determined already that NCoR can regulate their signaling. In the first Aim, we will determine if co-repressor specificity exists in vivo by analyzing the role of both NCoR and SMRT individually and together in context of thyroid hormone action in the liver. In the second Aim, we will focus on exploring the role of NCoR in both congenital hypothyroidism and resistance to thyroid hormone. Both of these human diseases are hypothesized to be due to aberrant co-repressor recruitment, though this has never been tested in vivo. In the third Aim, we will determine the role of NCoR in LXR-signaling both in the liver and in a variety of other key target issues. These studies will have direct applicability to the regulation of cholesterol metabolism in vivo. Interestingly, because LXR and TR intersect in the regulation of a number of key gene targets in cholesterol metabolism this Aim will also allow us to determine whether NCoR action is specific to a target NR. The completion of these three Aims will allow for greater comprehension of how modulation of co-repressor signaling in vivo alters key metabolic pathways. Furthermore this work should lead to novel insight into the target specificity of individual co-repressors and their role in key disease states that affect human health. PUBLIC HEALTH RELEVANCE: The transcriptional co-repressors, NCoR and SMRT, have been hypothesized to play a key role in a variety of human diseases including leukemia, congenital hypothyroidism, resistance to thyroid hormone (RTH), metabolic inflammation and hormone-related cancers because of their ability to be recruited to nuclear receptors. By focusing on the role of these co-repressors in their interactions with the thyroid hormone receptors and the liver x receptor we will gain insight into the mechanism by which these co-repressors function in the whole animal. In addition, our studies should shed new light on congenital hypothyroidism, RTH and hypercholesterolemia as our approach will directly test the role of co-repressors in these diseases.